Septic shock and related sequelae of infection are the most common causes of death in intensive care units. Deaths caused by sepsis can occur in previously healthy individuals, in all age groups, and in various common clinical settings. Some patients with common predisposing conditions are premature neonates, previously healthy children with acquired infections, teenagers and young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children and adults who acquire septic shock die from the syndrome. Thus septic shock imposes a great financial burden on society. Little is known about the organism virulence factors and toxins of this disease infection and factors related to the endogenous molecules that affect and modulate the inflammatory response. Thus, successful treatment of the septic shock syndrome will result from curing the infection and interrupting the effects of these organism and host mediators. Using purpose-bred beagles, the canine model of septic shock has provided information on the pathophysiology and treatment of the human disease. This model of acute and chronic infection simulates the course and cardiovascular changes seen routinely in children and adults with septic shock. Prior experiments using this model have established the role of specific bacteria (gram-positive and gram- negative), bacterial toxins (endotoxin), and host mediators tumor necrosis factor to produce septic shock. Several therapies are under investigation that might be effective in human septic shock. The canine model is ideally suited for preclinical trials of these new therapies, allowing properly controlled trials to evaluate therapeutic mechanisms and adverse effects of therapies. We are evaluating or have planned to evaluate the following therapies of septic shock in the canine model: tyrosine kinase inhibitors, bradykinin antagonists, dantrolene, soluble tumor necrosis factor receptor; antibodies to CD18 receptors on white blood cells; ibuprofen; antibody to tumor necrosis factor; granulocyte stimulating factor; antibodies to platelet activation factor; antibodies to Protein C; continuous A-V hemofiltration; high density lipoproteins; and platelet activating factor inhibitor.